Hepatocellular carcinoma (HCC) is highly aggressive and chemoresistant, severely limiting the clinical efficacy of current therapies. Methyltransferase-like 3 (METTL3), a key regulator of N6-adenosine methylation (m6A), is overexpressed in HCC and promotes its malignant progression, serving as a promising therapeutic target. siMETTL3 can specifically silence METTL3 but suffers from poor in vivo stability, nuclease degradation, and low delivery efficiency, hindering its clinical translation. To address these issues, we developed a reactive oxygen species (ROS)-responsive nanocarrier termed PEI-PBA-BSA for efficient siMETTL3 delivery, and systematically evaluated its physicochemical properties, tumour-targeting ability, and anti-HCC efficacy. Our results demonstrated that the nanocarrier encapsulated and protected siMETTL3. Through enhanced cellular uptake and ROS-triggered controlled release in the tumour microenvironment (TME), this nanocarrier efficiently silenced METTL3. In vitro, the nanoparticles significantly inhibited hepatoma cell proliferation, migration, invasion, and stemness. In vivo, the nanoparticles effectively suppressed tumour growth (with a tumour inhibition rate of up to 68%) and demonstrated good biosafety. In summary, PEI-PBA-BSA@siMETTL3 (PPB@siM3) represents a promising nanoplatform that mediates targeted and controlled siRNA release via TME-specific ROS responsiveness, overcoming core bottlenecks in traditional METTL3 gene therapy.

Although berberine possesses notable anti-inflammatory and antioxidant properties for ulcerative colitis (UC) treatment, its clinical utility is limited by poor oral bioavailability. To enhance berberine delivery, we engineered Eudragit® S100/Bletilla striata polysaccharide(EB)-coated berberine hydrochloride (BH)- hydrogenated soy phosphatidylcholine complex(HSPC) microspheres(MPs) a colon-targeted mucoadhesive micro‑nanocomposite. This system encapsulates a solubility-enhanced berberine‑phospholipid complex within microspheres coated with Eudragit® S100 and Bletilla striata polysaccharide (BSP). BSP serves a dual role as a bioadhesive carrier for prolonged mucosal retention and an immunoregulatory agent that synergizes with berberine. Utilizing electrospray and fluidized‑bed coating, the formulation achieved pH‑responsive, colon‑specific release. In vitro, the formulation exhibited favorable pH-dependent controlled release behavior, effectively scavenged reactive oxygen species, and promoted macrophage polarization towards the anti-inflammatory M2 phenotype. In DSS-induced acute and FXY-DSS-induced Spleen Deficiency chronic colitis models, EB@BH-HSPC significantly alleviated inflammation, restored intestinal barrier function, and attenuated oxidative stress, achieving improved therapeutic outcomes. It could be attributed to the synergy of berberine and BSP, combined with the integrated delivery advantages of improved solubility, precise colon targeting, and extended mucosal retention. In this system, BSP functions not only as an excipient but also as a synergistic therapeutic component with berberine. With its colon-targeting and mucoadhesive properties, the system provides a potent and integrated strategy for the treatment of ulcerative colitis.

Rheumatoid arthritis (RA) is a progressive autoimmune disorder marked by synovial inflammation and cartilage erosion. Conventional methotrexate (MTX) therapy suffers from poor joint targeting and systemic toxicity. This study developed exosome-mimicking liposomes (EMLs) for precision MTX delivery. The optimized formulation (F8), as determined by a 32 factorial design, had vesicle size of 101.4 ± 2.3 nm, encapsulation efficiency (EE) of 82.6 ± 2.4% and a zeta potential of –30.7 ± 1.2 mV. For 24 h, EMLs gave a consistent release pattern (73.4%), matching the kinetics observed using the Korsmeyer–Peppas model (R2 = 0.991). MTX taken up by cells was increased approximately 6-7 times higher than free MTX in RAW 264.7 cells. An in vivo study found that EMLs reached a Cmax value of 9.6 ± 0.48 µg/mL, had an AUC0–∞ of 54.3 ± 2.8 µg h/mL and showed 76.8% reduce in paw edema in collagen-induced arthritis animals. Histopathology analysis found that joints were better protected and there was decreased inflammation and cartilage damage. The results show that EMLs are a reliable and biocompatible way to carry out safe, effective and targeted treatment of rheumatoid arthritis.

ABSTRACT Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by memory loss and cognitive decline. This study aimed to develop and optimize an intranasal nanostructured lipid carrier (NLC) system co-loaded with Donepezil Hydrochloride (DPZ) and Caesalpinia bonduc seed extract (CBSE) to enhance therapeutic outcomes. LC-MS/MS profiling identified a CBSE bioactive compound with 93.16% structural similarity to neostigmine, suggesting synergistic cholinergic activity. NLCs were prepared using high-pressure homogenization and ultrasonication, optimized using Design of Experiments (DoE). The optimized NLCs exhibited an average particle size of 144.3 ± 1.78 nm, polydispersity index of 0.245 ± 0.025, and a zeta potential of –42.13 ± 2.14 mV, indicating uniformity and stability. TEM confirmed spherical morphology and particle size. The formulation showed high entrapment efficiency (67.27 ± 2.32%) with drug loading (16.81 ± 3.59%) and sustained drug release (72.43 ± 4.78%) over 5 h, following Zero-Order kinetics with Super Case II transport. Ex vivo nasal permeation studies showed significantly higher permeability (p < 0.05) than control, while histological analysis confirmed nasal mucosal safety. In vivo behavioral studies on AD-induced rats demonstrated significantly improved memory and cognition (p < 0.05) following nasal NLC administration. The DPZ-CBSE NLCs present a promising, safe, and non-invasive strategy for effective AD management.

Parkinson’s Disease (PD) is a prevalent neurodegenerative disorder. Recent studies implicate BRCA1-/BRCA2-containing complex 3 (BRCC3) in PD-related mechanisms such as ubiquitin-proteasome system dysfunction. This study aimed to evaluate the therapeutic potential of BRCC3 silencing via systemically administered siRNA-loaded niosomes in a rotenone-induced rat model of PD. Niosomes were synthesised by thin-film hydration, and three BRCC3-targeted siRNA sequences were tested in primary midbrain dopaminergic neurons. The most effective sequence, identified by Real-Time Quantitative PCR (RT-qPCR) and immunofluorescence, was used for in vivo studies. The PD model was induced in adult male rats (n = 24/group) by subcutaneous rotenone administration (2 mg/kg/day) for 35 days. In the in vivo phase of the study, behavioural, biochemical, in vivo imaging (IVIS), histological, and RT-qPCR analyses were performed. IVIS analysis confirmed brain accumulation of niosome-siRNA complexes within 3–5 h. Complementary analyses demonstrated that siRNA treatment significantly enhanced locomotor performance, restored redox homeostasis and dopamine levels, attenuated neuronal loss, upregulated autophagy-related proteins (↑LC3-II, ↑Beclin), suppressed endoplasmic reticulum stress markers (↓GRP78/Bip, ↓CHOP), elevated tyrosine hydroxylase expression, and reduced α-synuclein accumulation. In conclusion, siRNA-mediated suppression of BRCC3 via siRNA-loaded niosomes provides neuroprotection by modulating autophagy, ER stress, and antioxidant pathways, supporting BRCC3 as a promising therapeutic target for PD.

A novel local chemotherapy delivery system was developed to improve the therapeutic efficacy of paclitaxel (PTX) for osteosarcoma while reducing systemic toxicity, low bioavailability, and tumor recurrence. PTX-loaded polylactic-co-glycolic acid nanoparticles (PLGA/PTX) were fabricated by an emulsification solvent evaporation method. Meanwhile, low-immunogenicity bone extracellular matrix (ECM) was prepared from porcine/bovine femurs through gradient decellularization combined with physical, chemical, and enzymatic treatments, followed by pepsin digestion to create a temperature-responsive injectable hydrogel. PLGA/PTX nanoparticles were incorporated into the bone ECM pre-gel to form a composite hydrogel system (H@PLGA/PTX). The processed bone ECM achieved over 97% decellularization while preserving collagen structure and biocompatibility. The composite hydrogel exhibited a porous three-dimensional network and released 62.5 ± 4.5% of PTX within 48 hours under mildly acidic conditions (pH 6.5). In vitro assays showed superior anti-tumor effects against MG-63 osteosarcoma cells compared with free PTX. In vivo studies demonstrated significant tumor inhibition, stable body weight, and prolonged survival, associated with enhanced Caspase-3–mediated apoptosis. Overall, H@PLGA/PTX provides sustained local drug release with strong anti-tumor activity and low systemic toxicity, offering a promising strategy for adjuvant osteosarcoma chemotherapy.

Objective To develop and optimise a VEN nasal thermosensitive in-situ gel for reducing the first-pass effect and enhancing bioavailability. Methods High performance liquid chromatography, central composite design-response surface methodology, the membrane-free erosion and the Franz vertical diffusion cell method were used to clarify the optimised formulation. Pharmacokinetic and pharmacodynamic studies evaluated sustained release and efficacy. Results The optimal formulation (32.87-33.17 °C gelation temp) comprised 12.5% w/v VEN, 20.44% w/v poloxamer 407, 0.74% w/v P188, 5% w/v 2-Hydroxypropyl-β-cyclodextrin, 0.5% w/v hydroxypropyl methyl cellulose, 0.12% w/v potassium sorbate, 10% v/v glycerol, and 90% v/v water; it had a good stability and sustained-release effect of VEN and increased bioavailability and reduced O-desmethylvenlafaxine production. It achieved 90% cumulative release at 15h in vitro, and its intranasal Cmax was higher than oral VEN (p < 0.05) without detectable O-desmethylvenlafaxine. Treatment with VEN thermosensitive in-situ gel in a depressive rat model improved the sucrose preference rate in the sucrose preference test and the total distance of movement in the open field test, also significantly increased the level of 5-hydroxytryptamine and norepinephrine in the hippocampus (p < 0.01). Conclusion This innovative P407/P188-based gel enhances VEN bioavailability and antidepressant efficacy via sustained release and brain targeting, providing critical data for nasal formulation development.

Skin cancer is caused by excessive UVR exposure, which poses a serious health risk. The use of phytoconstituents as medicaments for the management of various diseases has been trending in recent years due to their fewer adverse effects than synthetic medicines. Naringenin (NG) is a natural polyphenol and a potent antioxidant, with remarkable ROS-scavenging and UVR-protection potential. However, NG exhibits limitations in bioavailability, permeability, stability and half-life. We address this drawback with a novel approach to formulate NG-loaded niosomes as a ligand-specific nanocarrier system. A modified thin-film hydration technique and a Box-Behnken experimental design were used to formulate and optimise NG-loaded niosomes (NG-Nio), respectively. The optimised NG-Nio and Mn-NG-Nio formulations were further characterised for vesicular size, ZP, DE, DL and mannose content. Furthermore, the incorporation of Mn-NG-Nio into a topical gel formulation. The Mn-NG-Nio-gel was characterised for rheological properties, spreadability, in vitro drug release and skin permeation. An in vitro cytotoxicity assay demonstrated higher cellular uptake and significant dose-dependent activity across different cell lines. The in vivo study showed significant reductions in myeloperoxidase levels and in UVB-induced 4-HNE and COX-2 protein levels. The research highlights the potential of Mn-NG-Nio for targeting skin cancer cells, reducing UVB-induced inflammation and oxidative stress.

ABSTRACT Chemoresistance is a primary factor contributing to chemotherapy failure in breast cancer. Combining chemotherapeutic agents with nucleic acids that interfere with drug resistance-related genes can effectively overcome chemoresistance in breast cancer. However, the stark differences in key physicochemical properties such as hydrophobicity versus hydrophilicity and surface charge, along with their divergent pharmacokinetic profiles, significantly compromise the synergistic therapeutic potential. Co-delivery nanocarriers enable the encapsulation of both chemotherapeutic agents and nucleic acids within a single carrier, which facilitates simultaneously and spatiotemporally targeted and controlled delivery and represents a promising strategy for treating chemoresistant breast cancer. This review summarized the progress of polymer, lipid, and inorganic materials used in the co-delivery of chemotherapeutic drugs and nucleic acids, with a focus on major advances achieved over the past decade. The critical challenges in the design and optimization, clinical translation of these co-delivery systems, and insights for future research were also discussed.

Endocrinologists and nephrologists continually seek new therapeutic approaches for diabetic nephropathy (DN). Lately, mesenchymal stem cell (MSC)-derived exosomes (MSC-EXs) have been applied as natural carriers for targeted drug delivery. Thus, we aim to estimate the therapeutic potential of MSCs-EXs loaded with elemental selenium (Se) or its nanoform (NSe) as a promising cell-free therapy for DN. Eighty rats were split into 8 groups; control, EXs, EXs + Se, EXs + NSe, diabetic (D), D + EXs, D + EXs + Se, and D + EXs + NSe. After 4 weeks, our results indicated that unloaded or loaded EXs with Se or NSe had renal ameliorating effects, as evidenced by significantly decreased serum levels of urea, uric acid, and creatinine compared to untreated diabetics. Such observations might be a reflection of the observed antioxidant activity of both EXs alone or in the combined form with either Se or NSe, evidenced by markedly decreased renal MDA, NO, H2O2 levels coupled with increased GSH, SOD, CAT, and GPX, besides their anti-inflammatory and antiapoptotic effects, indicated by the decreased renal levels of IL-6, TGF-β, TNF-α, BAX, caspase-3, and P53, with Bcl-2 upregulation. Consequently, the kidney architecture in all diabetic-treated groups was greatly improved. Likely, the EX-loaded NSe treatment protocol highlighted the DN improvement superiority over the other two treatments.